RT Journal Article SR Electronic T1 Characterization of the Anxiolytic Properties of a Novel Neuroactive Steroid, Co 2-6749 (GMA-839; WAY-141839; 3α, 21-Dihydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one), a Selective Modulator of γ-Aminobutyric AcidA Receptors JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 337 OP 345 VO 295 IS 1 A1 Kimberly E. Vanover A1 Sharon Rosenzweig-Lipson A1 Jon E. Hawkinson A1 Nancy C. Lan A1 James D. Belluzzi A1 Larry Stein A1 James E. Barrett A1 Paul L. Wood A1 Richard B. Carter YR 2000 UL http://jpet.aspetjournals.org/content/295/1/337.abstract AB The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3α, 21-dihydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one), on γ-aminobutyric acidA receptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [35S]t-butylbicyclophosphorothionate binding in rat brain cortical membranes with an IC50 value of 230 nM and in human γ-aminobutyric acidA receptor subunit combinations of α1β2γ2L, α2β2γ2L, α3β2γ2L, α4β3γ2L, α5β2γ2L, and α6β3γ2L receptors (IC50 values of 200, 200, 96, 2300, 210, and 2000 nM). Rats were trained in a Geller-Seifter operant conflict paradigm. Co 2-6749 caused a dose-related increase in punished responding with a minimum effective dose of 1.6 mg/kg, p.o., a wide therapeutic index relative to a decrease in unpunished responding and relative to ataxia, and no tolerance. Additionally, ethanol caused less than a 2-fold shift to the left in the dose-response function of Co 2-6749 in the rotorod procedure in rats. In a pigeon conflict paradigm, punished responding was maximally increased to 784% of vehicle control by 30 mg/kg, p.o., with a 2-h duration and no effect on unpunished responding at this dose. Similarly, punished responding in squirrel monkeys was maximally increased to 1774% of control by 10 mg/kg, p.o., with no effect on unpunished responding at this dose. With robust anxiolytic-like activity across species, a large separation between anxiolytic-like effects and sedation/ataxia, a minimal interaction with ethanol, a lack of tolerance, and apparent oral bioavailability, Co 2-6749 makes an ideal candidate for development as a novel anxiolytic drug. The American Society for Pharmacology and Experimental Therapeutics